Advances in genome technology and their increased use in translational research have increased our current understanding of Myelomagenesis.The goal of my research is to interrogate the myeloma genome to elucidate mechanisms of drug resistance to anti-MM agents, identify druggable therapeutic targets in myeloma and discover new biomarkers of response to novel agents. In addition over the past 5 years I have also focused on identifying biomarkers for a better targeting of therapeutics in this disease and the delivery of individualized medicine. As such, I have established in Calgary a Myeloma tissue bank that consists of a library of bone marrow biopsies from myeloma patients as well genomic materials to interrogate the genome of primary myeloma cells and define mechanisms of drug resistance. As such we have shown that loss of cereblon (CRBN) or increased expression of a CRBN splice isoform lacking exon 10, are associated with resistance to immunomodulatory drugs. Defining the exact mechanisms that mediate the efficacy or resistance to this class of drug in myeloma will surely permit to design therapeutic strategies to maximize their therapeutic potential and possibly overcome drug resistance. Moreover, studying the chromosomal instability of myeloma cells we have identified a novel therapeutic approach that relies on the contextual synthetic lethality between proteasome and PARP inhibitors. We have demonstrated that the proteasome inhibitor bortezomib induces a BRCAness state in MM cells and results in a contextual synthetic lethality when combined with PARP inhibitors. This work was translated into the clinic with recently completed phase I clinical trial combining bortezomib with veliparib in multiply relapsed myeloma patients. This work has led to the understanding that targeting DNA repair defects present only in tumor cells can represent a promising area of clinical investigation in Multiple Myeloma.
University Of Calgary Arnie Charbonneau Cancer Institute:
Art Building, 2500 University Dr NW, Calgary, AB T2N 1N4, Canada
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